Anna Sutela

Poor Cognitive Outcome in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus

BACKGROUND Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. OBJECTIVE To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. METHODS The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. RESULTS At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition. CONCLUSION The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH-related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities.

Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature.

V. Leinonen, A. M. Koivisto, S. Savolainen, J. Rummukainen, A. Sutela, R. Vanninen, J. E. Jääskeläinen, H. Soininen and I. Alafuzoff (2012) Neuropathology and Applied Neurobiology38, 72–86

Axillary Lymph Node Biopsy in Newly Diagnosed Invasive Breast Cancer: Comparative Accuracy of Fine-Needle Aspiration Biopsy versus Core-Needle Biopsy

PURPOSE To compare the diagnostic accuracy of ultrasonographically (US)-guided fine-needle aspiration biopsy (FNAB) and core-needle biopsy (CNB) of the axillary lymph nodes (LNs) of patients with newly diagnosed invasive breast cancer. MATERIALS AND METHODS This prospective single-center study had institutional review board approval, and written informed consent was obtained. Between April 2011 and March 2012, 178 consecutive patients (182 axillae) were evaluated by using axillary US. Sixty-six axillae fulfilled the inclusion criteria (cortical thickness greater than 2 mm or abnormal morphologic characteristics), and patients with these axillae underwent US-guided axillary LN biopsy. Both FNAB and CNB were obtained from the same suspicious LN. Patients with biopsy-proved metastasis underwent axillary clearance, and those with a negative biopsy underwent sentinel LN biopsy with completion axillary clearance if needed. Diagnostic performance was calculated separately for US, FNAB, and CNB. Statistical differences in sensitivities were evaluated by using the McNemar test. RESULTS From the total study population, 45.6% (83 of 182 axillae) had metastases. A total of 66 axillae underwent both FNAB and CNB. The sensitivity for US was 61.4% (51 of 83 axillae), and specificity was 84.8% (84 of 88 axillae). The sensitivities for FNAB and CNB were 72.5% (37 of 51 axillae) and 88.2% (45 of 51 axillae), respectively (P = .008). Specificity for both was 100% (15 of 15 axillae). The negative predictive value for FNAB was 81.7%, and that for CNB was 91.2%. The positive predictive value was 100% for both methods. CONCLUSION When accurate preoperative staging of the axilla is needed in patients with newly diagnosed invasive breast cancer, CNB is more sensitive than FNAB.

Surgical specimen can be replaced by core samples in assessment of ER, PR and HER-2 for invasive breast cancer

Objective. To compare 14-gauge SCNB (stereotactic core needle biopsy) with surgery and to investigate tissue-heterogeneity of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth-factor receptor (HER-2) for non-palpable breast cancers. To determine the number of cores needed for assessment of these factors. Materials and methods. Cores of 41 invasive cancers were collected in three containers: the 1st into A, the 2nd and 3rd into B and subsequent cores into C. ER, PR and HER-2 were scored by immunohistochemistry and if 2+ or 3+, by chromogenic-in-situ-hybridisation (CISH) for containers and for surgical specimen. Results. Between SCNB and surgical specimen concordance was 83% (κ=0.39) for ER, 88% (κ=0.69) for PR and HER-2 and 93% (κ=0.63) for HER-2 after CISH. For the most discordant cases, status was positive in cores but negative in surgery: 5/7 for ER (p=0.459), 5/5 for PR (p=0.063), and 4/5 for HER-2 (p=0.375), after CISH 3/3 (p=0.250), but the difference was not statistically significant. Concordances between containers of cores was 100% (κ=1), 85% (κ=0.66) and 85% (κ=0.66), respectively. With more than three cores, sensitivities of 95%, 100% and 100% were reached. Conclusions. SCNB is at least as sensitive as surgery in assessment of ER, PR and HER-2. Three cores are needed for reliable assessment of HER-2 after adding CISH and more than three cores for PR, possibly due to tissue heterogeneity. For ER sensitivity remained lower, 95%, even in multiple cores, therefore ER-negative cases should be further investigated from surgical specimens.

Diffusion-Weighted Imaging in 3.0 Tesla Breast MRI: Diagnostic Performance and Tumor Characterization Using Small Subregions vs. Whole Tumor Regions of Interest

Introduction Apparent diffusion coefficient (ADC) values are increasingly reported in breast MRI. As there is no standardized method for ADC measurements, we evaluated the effect of the size of region of interest (ROI) to diagnostic utility and correlation to prognostic markers of breast cancer. Methods This prospective study was approved by the Institutional Ethics Board; the need for written informed consent for the retrospective analyses of the breast MRIs was waived by the Chair of the Hospital District. We compared diagnostic accuracy of ADC measurements from whole-lesion ROIs (WL-ROIs) to small subregions (S-ROIs) showing the most restricted diffusion and evaluated correlations with prognostic factors in 112 consecutive patients (mean age 56.2±11.6 years, 137 lesions) who underwent 3.0-T breast MRI. Results Intra- and interobserver reproducibility were substantial (κ = 0.616–0.784; Intra-Class Correlation 0.589–0.831). In receiver operating characteristics analysis, differentiation between malignant and benign lesions was excellent (area under curve 0.957–0.962, cut-off ADC values for WL-ROIs: 0.87×10−3 mm2s-1; S-ROIs: 0.69×10−3 mm2s-1, P<0.001). WL-ROIs/S-ROIs achieved sensitivities of 95.7%/91.3%, specificities of 89.5%/94.7%, and overall accuracies of 89.8%/94.2%. In S-ROIs, lower ADC values correlated with presence of axillary metastases (P = 0.03), high histological grade (P = 0.006), and worsened Nottingham Prognostic Index Score (P<0.05). In both ROIs, ADC values correlated with progesterone receptors and advanced stage (P<0.01), but not with HER2, estrogen receptors, or Ki-67. Conclusions ADC values assist in breast tumor characterization. Small ROIs were more accurate than whole-lesion ROIs and more frequently associated with prognostic factors. Cut-off values differed significantly depending on measurement procedure, which should be recognized when comparing results from the literature. Instead of using a whole lesion covering ROI, a small ROI could be advocated in diffusion-weighted imaging.

Contrast-enhanced ultrasound -guided axillary lymph node core biopsy: Diagnostic accuracy in preoperative staging of invasive breast cancer.

OBJECTIVES To evaluate accuracy of contrast enhanced ultrasound (CEUS)-sentinel procedure followed by core biopsy (CB) and marking in patients with breast cancer. To compare the axillary metastatic tumour burden in patients with positive vs. negative CB results. METHODS Two radiologists in our tertiary care hospital performed axillary CEUS sentinel procedures on consecutive US node negative breast cancer patients. The first enhancing lymph node (LN) was core biopsied and marked with a breast coil. The results were compared to final histopathology. We analysed the diagnostic performance of CEUS CB and its ability to detect patients with higher axillary burden (>2 metastasis). RESULTS During the study period between January 2013 and December 2014, altogether 54 patients (mean age 60.4 years) were included in the statistical analysis. The sensitivity for CEUS CB was 66.7%, specificity 100%, PPV 100%, NPV 93.8% and overall accuracy 94.4%. The method correctly recognised all the axillae with higher tumour burdens (sensitivity 100%, N=3) and 59.3% of coils marking the LNs were discovered. CONCLUSION CEUS -guided axillary CB proved to be feasible and accurate procedure with moderate sensitivity and it clearly identified the higher axillary tumour burden. The coil marking of LNs as used cannot be recommended. In clinical routine, CEUS procedure might be recommended in selective patient populations.

High Risk of Dementia in Ventricular Enlargement with Normal Pressure Hydrocephalus Related Symptoms1.

BACKGROUND Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known. OBJECTIVES We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH. METHODS A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years. RESULTS Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimers disease (n = 94, 36%), followed by vascular dementia (n = 68, 26%). CONCLUSIONS One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized.

Preoperative axillary staging with 3.0-T breast MRI: clinical value of diffusion imaging and apparent diffusion coefficient.

The axillary staging in newly diagnosed breast cancer is under major evolution. The aims of this study were to define the diagnostic performance of 3.0-T diffusion-weighted imaging (DWI) in the detection of axillary metastases in newly diagnosed breast cancer, to assess apparent diffusion coefficients (ADCs) for histopathologically confirmed metastatic lymph nodes in a clinical setting. Altogether 52 consecutive breast cancer patients underwent magnetic resonance imaging and DWI in addition to axillary ultrasound. ADCs of axillary lymph nodes were analysed by two breast radiologists and ultrasound-guided core biopsies were taken. In a separate reading by one radiologist two types of region of interests were used for a smaller group of patients. Altogether 56 axillae (121 lymph nodes) were included in the statistical analysis. Metastatic axillae (51.8%) had significantly lower ADCs (p<0.001). Mean ADCs were 0.663–0.676 x 10-3 mm2/s for the histologically confirmed metastatic LNs and 1.100–1.225 x 10-3 mm2/s for the benign. The sensitivity, specificity, and accuracy of DWI were 72.4%, 79.6%, and 75.9%, respectively with threshold ADC 0.812 x 10-3 mm2/s. Region of interest with information on the minimum value increased the diagnostic performance (area under the curve 0.794 vs. 0.619). Even though ADCs are significantly associated with histopathologically confirmed axillary metastases the diagnostic performance of axillary DWI remains moderate and ultrasound-guided core biopsies or sentinel lymph node biopsies cannot be omitted.

Multimodal analysis to predict shunt surgery outcome of 284 patients with suspected idiopathic normal pressure hydrocephalus

ObjectivesOptimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer’s disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH.MethodsIn this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients’ memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure.ResultsOur analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC = 0.58).ConclusionsPrediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.

UDP-sugar accumulation drives hyaluronan synthesis in breast cancer

Increased uptake of glucose, a general hallmark of malignant tumors, leads to an accumulation of intermediate metabolites of glycolysis. We investigated whether the high supply of these intermediates promotes their flow into UDP-sugars, and consequently into hyaluronan, a tumor-promoting matrix molecule. We quantified UDP-N-Acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcUA) in human breast cancer biopsies, the levels of enzymes contributing to their synthesis, and their association with the hyaluronan accumulation in the tumor. The content of UDP-GlcUA was 4 times, and that of UDP-GlcNAc 12 times higher in the tumors as compared to normal glandular tissue obtained from breast reductions. The surge of UDP-GlcNAc correlated with an elevated mRNA expression of glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), one of the key enzymes in the biosynthesis of UDP-GlcNAc, and the expression of GFAT1 was also elevated. The contents of both UDP-sugars strongly correlated with tumor hyaluronan levels. Interestingly, hyaluronan content did not correlate with the mRNA levels of the hyaluronan synthases (HAS1-3), thus emphasizing the role of the UDP-sugar substrates of these enzymes. The UDP-sugars showed a trend to higher levels in ductal vs. lobular cancer subtypes. The results reveal for the first time a dramatic increase of UDP-sugars in breast cancer, and suggest that their high supply drives the accumulation of hyaluronan, a known promoter of breast cancer and other malignancies. In general, the study shows how the disturbed glucose metabolism typical for malignant tumors can influence cancer microenvironment through UDP-sugars and hyaluronan.